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Biomedical subjects

B Christensen

Publications and source records attributed to B Christensen.

At least 55 records · Page 3Linked to original sources
PubMed1999

Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects.

Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A-->G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28-5.13) for being a case and of 3.05 (95% CI 1.54-6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49-72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84-12.85). We propose that the genetic-nutrient interaction--MTHFR polymorphism and low folate status--is associated with a greater risk for NTDs than either variable alone.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

Isotopomer analysis using GC-MS.

Knowledge of the complete isotopomer distribution represents the ultimate amount of information on the labeling pattern of a metabolite. One technique for measuring the isotopomer distributions is the analysis of the multiplet intensities arising from the 13C-13C couplings in NMR spectroscopy. While this technique has proven to be very valuable in the elucidation of labeling patterns of C2 and C3 units of various amino acids, fragments larger than C3 are very difficult to measure. Another technique, GC-MS, offers a unique possibility of analyzing fragments larger than C3 and GC-MS is therefore able to give information which is complementary to the information that can be obtained from NMR spectroscopy. In this work we have developed fast, simple, and robust GC-MS methods that can be used to gain information on the labeling patterns of the amino acids in a crude biomass hydrolysate. It is shown that a combination of information obtained from these analyses and information from the NMR spectroscopy is able to yield a much more complete picture of the isotopomer distributions of the amino acids than any of the two techniques alone. The GC-MS method was used for analyzing the labeling patterns of amino acids from a batch cultivation of Penicillium chrysogenum grown on fully labeled glucose. The data from this analysis showed no signs of any significant carbon isotope effects, and the measurements can therefore be used without corrections for metabolic flux analysis.

Amino Acids↗
PubMed1999

A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.

Impairment of folate and cobalamin (vitamin B(12)) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C-->T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A-->G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95% CI 0.58-14.8). This study provides the first genetic link between vitamin B(12) deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

Whole blood folate, homocysteine in serum, and risk of first acute myocardial infarction.

High level of total homocysteine (tHcy) is a risk factor for coronary artery disease (CAD), but the mechanism is not known. The serum concentration of tHcy, total cholesterol, high density lipoprotein cholesterol (HDL-C), and apolipoprotein A-I (apo A-I) and the concentration of folate in whole blood were measured in 107 patients with first acute myocardial infarction (MI) and 103 controls. The level of whole blood folate was lower and that of tHcy higher in cases than in controls. An increase of 50 nmol/l whole blood folate was associated with an OR for MI of 0.75, and an increase of 5 micromol/l tHcy with an OR for MI of 1.57. Correlations were observed between the levels of whole blood folate and tHcy and between whole blood folate and alcohol intake, and in MI cases, between tHcy, HDL-C, and apo A-I as well as between HDL-C and alcohol intake. The number of cigarette smokers was higher among cases than controls. In smokers, the level of tHcy was higher and that of whole blood folate lower than in non-smokers. After adjustment for smoking, the whole blood folate and tHcy-associated risks of MI became non-significant. We conclude that smoking may affect folate status and tHcy level adversely. The risk of MI in smokers may at least partly be attributed to hyperhomocysteinemia or low folate.

Age Distribution↗
PubMed1999

Endometriosis: a clinically malignant disease.

According to the literature this is the first patient with the primary diagnosis of an endometriosis (EMT) based on the cardinal symptom of an uremia in combination with a colorectal ileus. Operative removal of EMT was possible after hormonal suppression with Dienogest.

Adult↗
PubMed1999

Health education pamphlets about smoking--their benefit to smokers and non-smokers.

The aim of this present study was to compare the use by smokers and non-smokers of pamphlets about smoking as delivered from different settings. The study was a nation-wide cross-sectional survey of 1924 randomly selected, Danish men and women, aged 14-77 y, who had answered a mailed questionnaire in 1994. Of these 71% also participated in a telephone interview enquiring about the use of health education material, smoking status and socio-demographic variables, 39% of readers of household-delivered anti-smoking pamphlets reported having gained information from them and 22% reported having made changes in their own smoking behaviour such as avoiding smoking in the presence of non-smokers. In general practice settings, these percentages were higher among smokers. Smokers who were thinking of stopping smoking in the near future were in addition more likely to take and to read smoking related health education materials from other places. Non-smokers received (3 49%) and read pamphlets about smoking as frequently as did smokers who did not intend to quit. In conclusion, written health education material was well received by readers, but, when distributed in a more open setting it needs to be targeted towards smokers who are considering stopping smoking. In general practice, smokers not thinking of stopping were open to health education, and pamphlets used in this setting should also target this group. Non-smokers contribute indirectly to smokers quitting by providing support to smokers and pamphlets for non-smokers need to be more targeted towards this social role.

Adolescent↗
PubMed1999

Prevalence of hereditary hearing impairment in adults.

This contribution, part of an EU-Concerted Action on the genetics of hearing impairment (H.E.A.R.), describes the preliminary estimated prevalence of hereditary hearing impairment based on retrospective data from a clinical series. Of 27,692 subjects examined in the period 1987-91, we sampled 1265 suffering from unilateral or bilateral hereditary hearing impairment, which is roughly 5% of those examined (n = 384 (31%) male; n = 881 (69%) female). Median age of the subjects is 70 years (range 22-98). Subdividing them into 10-year birth cohorts and applying the local annual population statistics, the prevalence of an overall age-related hereditary hearing impairment was roughly estimated to be 3.2/1000, reflecting prevalences as a function of age from 0.8 to 9.4/1000--prevalence in females being significantly more than in males (4.1/1000 and 2.1/1000, respectively). Overall, a moderate hearing impairment of median 51 dB in the better hearing ear was found, averaged across 0.5-4 kHz, this being fairly constant up to the age of 60, when a significant reduction in hearing sensitivity developed. No significant differences are present as a function of gender, except for the birth cohorts 1910-19 and 1920-29. The most frequent type of hereditary hearing impairment in this sample is otosclerosis, comprising 2% of the total clinical series with a rough population prevalence estimate of 1.4/1000. It is concluded that the established database may be of importance in the aggregation of very rare diseases, and for providing the inspiration for future prospective population studies, resulting in knowledge on the epidemiology of hereditary hearing impairment in adults.

Adult↗
PubMed1999

A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk.

We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

Altered serum concentrations of TGF-beta 1 and Lp(a) lipoprotein and their correlation in patients with first acute myocardial infarction.

BACKGROUND AND AIM: The association between high plasma Lp(a) lipoprotein and coronary heart disease has been confirmed in numerous case/control and prospective studies. A high Lp(a) level has also been shown to be an independent genetic risk factor, while its inverse relationship with TGF-beta 1 has suggested that it may interfere with plasmin-mediated activation of TGF-beta 1 and result in increased endothelial activation, as well as migration and proliferation of vascular smooth muscle cells. The aim of this study was to evaluate Lp(a) and TGF-beta 1 and their interactions in patients with first acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 107 patients with first AMI and 103 age and sex-matched controls were studied. Very good agreement was found between QEI and RIA determinations of Lp(a) (p < 0.0001). Lp(a) levels were significantly elevated in cases (QEI: p < 0.031; RIA p < 0.002 respectively). Division by gender gave statistically significant differences in females only. Plasma levels of the active form of TGF-beta 1 were decreased in cases, though significantly (p < 0.029) in males only. CONCLUSIONS: Serum concentrations of Lp(a) and TGF-beta 1 are significantly altered in AMI patients. The differences are gender-dependent: Lp(a) is higher in females, and TGF-beta 1 is lower in males. Increased Lp(a) levels are accompanied by decreased active TGF-beta 1 levels and this inverse correlation is statistically significant (p < 0.001).

Aged↗
PubMed1998

[Magnetic tomography of the central nervous system in adults with myelomeningocele].

The Norwegian training and counselling centre for patients with rare disabilities is a national project with the aim of developing new models for services designed to improve the quality of life of these patients. As at 1 July 1997, 130 adults with myelomeningocele were registered users of the Centre. This article is a retrospective review of reports from MRI evaluations of the central nervous system of 61 (40%) of the centre's users, performed in seven departments of radiology. Caput, the craniocervical region and distal parts of the medulla were the most frequently examined areas; the thoracal medulla was examined in half of the cases. There were considerable differences with respect to the structures examined. Enlargement of the lateral ventricles was as frequent in patient without shunt (68%) as in patients with shunt (53%). Dysmorphology of the corpus callosum was seen in 39%. Intracranial structural abnormalities were often described without a report on the intracranial pressure. Herniation of the cerebellar tonsils was reported in 66% of patients, tethering of the spinal cord in 90%, and syringomyelia in 13%. In most cases, MT uncovered conditions with implications for management. We suggest that standard routines should be developed for examinations of the central nervous system of patients with myelomeningocele.

Adolescent↗
PubMed1998

[The significance of associated malformations of the central nervous system in myelomeningocele].

Neural tube defects are the most frequent congenital structural malformations in Norway. Approximately half of these are myelomeningocele. Infants with myelomeningocele frequently have hydrocephalus at birth. Problems with intracranial pressure may as well develop later. There are several reports on pathological corpus callosum and an increasing number of reports on cognitive problems in patients with myelomeningocele. Most patients with myelomeningocele have a tethered spinal cord, and some have syringomyelia. Chiari malformation type II is a malformation of the skull and brainstem which is frequently observed in individuals with myelomeningocele. Chiari malformation may cause severe respiratory problems in infants. Chiari malformation, tethered cord as well as syringomyelia are associated with a range of neurological problems which may progress in adulthood. Surgical intervention may improve the situation. Anaesthesia may induce neurological complications in individuals with Chiari malformation or syringomyelia. Since pregnancy and childbirth are associated with complications, women with myelomeningocele should be examined before they become pregnant. Children and adults with myelomeningocele should routinely undergo MRI examinations of caput and the spinal cord to clarify their anatomical situation.

Abnormalities, Multiple↗
PubMed1998

[New diagnostic criteria in Marfan syndrome].

Marfan's syndrome is a relatively frequent autosomal dominant condition which is due to structural or quantitative changes in a connective tissue protein, fibrillin. The syndrome is associated with life-threatening changes in the aorta and serious manifestations in many different organ systems. Unclear diagnostic criteria and lack of use of the criteria in clinical practice may have led to overdiagnosing this syndrome in individuals with a long and slender habitus. This in turn can lead to negative consequences for both the individual and his or her family. Failure of diagnosis may cause even more harm, in particular because of the risk of sudden cardiac events. In 1996 an international group of experts proposed a set of revised criteria for Marfan's syndrome which takes into account molecular findings and family history (the Gent criteria). It is important that all practising physicians are aware of these criteria in order to prevent over- and underdiagnosing. A correct diagnosis is of major importance for medical follow-up, genetic counselling, habilitation, and counselling with regard to education and occupation.

Diagnosis, Differential↗
PubMed1998

[Molecular biology diagnostics of hereditary metabolic diseases].

Metabolic diseases are often a result of monogenic inheritance and are suitable subjects for molecular diagnosis. Much progress has been made on research into this group of diseases, and further advances are expected after the completion of the Human Genome Project (HUGO) and as a consequence of improved molecular genetic methods. Although it is possible to diagnose many metabolic disorders by biochemical analyses of enzyme function, the underlying molecular genetic defects must be identified in order to be able to make accurate diagnoses of patients and their relatives. A molecular diagnosis is also a pre-condition for gene therapy. It is of paramount importance that more knowledge is gained of the correlation between genotype and phenotype for the genetic counselling of patients and their families. Important challenges at the present time are how to achieve a better understanding of the molecular and metabolic basis for the way in which diseases manifest themselves clinically and the factors which modify the phenotype.

DNA Mutational Analysis↗
PubMed1998

A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%).

Adult↗
PubMed1998

Ontogenetic scaling of foraging rates and the dynamics of a size-structured consumer-resource model.

The ontogenetic scaling of foraging capacity strongly influences the competitive ability of differently sized individuals within a species. We develop a physiologically structured model to investigate the effect of different ontogenetic size scalings of the attack rate on the population dynamics of a consumer-resource system. The resource is assumed to reproduce continuously whereas the consumer only reproduces at discrete time instants. Depending on the ontogenetic size scaling, the model exhibited recruit-driven cycles, stable fixed point dynamics, non-recruit juvenile-driven cycles, quasiperiodic orbits, or chaotic dynamics. The kind of dynamics observed was related to the maintenance resource levels required of differently sized individuals. Stable fixed point dynamics was, besides at the persistence boundary, only observed when the minimum resource levels were similar for newborns and mature individuals. The tendency for large population fluctuations over a wide range of the parameter space was due to the consumer's pulsed reproduction. Background mortality and length of season were major determinants of cycle length. Model dynamics strongly resembled empirically observed dynamics from fish and Daphnia populations with respect to both patterns and mechanisms. The non-recruit juvenile-driven dynamics is suggested to occur in populations with size-dependent interference or preemptive competition like cicada populations.

Animals↗
PubMed1997

A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease.

The predominant genetic defect causing p47-phox-deficient chronic granulomatous disease (A47 degrees CGD) is a GT deletion (DeltaGT) at the beginning of exon 2. No explanation exists to account for the high incidence of this single mutation causing a rare disease in an unrelated, racially diverse population. In each of 34 consecutive unrelated normal individuals, both the normal and mutant DeltaGT sequences were present in genomic DNA, suggesting that a p47-phox related sequence carrying DeltaGT exists in the normal population. Screening of genomic bacteriophage and YAC libraries identified 13 p47-phox bacteriophage and 19 YAC clones. The GT deletion was found in 11 bacteriophage and 15 YAC clones. Only 5 exonic and 33 intronic differences distinguished all DeltaGT clones from all wild-type clones. The most striking differences were a 30-bp deletion in intron 1 and a 20-bp duplication in intron 2. These results provide good evidence for the existence of at least one highly homologous p47-phox pseudogene containing the DeltaGT mutation. The p47-phox gene and pseudogene(s) colocalize to chromosome 7q11.23. This close linkage, together with the presence within each gene of multiple recombination hot spots, suggests that the predominance of the DeltaGT mutation in A47 degrees CGD is caused by recombination events between the wild-type gene and the pseudogene(s).

Bacteriophages↗